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Optogenetics and Its Application in Neural Degeneration and Regeneration

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Optogenetics and Its Application in Neural Degeneration and Regeneration 3/13/2018 Optogenetics and its application in neural degeneration and regeneration Neural Regen Res. 2017 Aug; 12(8): 1197–1209. PMCID: PMC5607808 doi: 10.4103/1673-5374.213532 Optogenetics and its application in neural degeneration and regeneration Josue D. Ordaz,1,2,3 Wei Wu,1,2,3 and Xiao-Ming Xu, M.D., Ph.D.1,2,3,4,* 1 Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA 3 Goodman Campbell Brain and Spine, Indianapolis, Indiana, USA 4 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA * Correspondence to: Xiao-Ming Xu, [email protected]. Author contributions: JDO wrote the paper. JDO and WW were responsible for making figures and edited the paper. XMX reviewed and edited the paper. All authors participated in the conception of this study and approved the final version of this paper. Accepted 2017 Jul 11. Copyright : © Neural Regeneration Research This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. Abstract Neural degeneration and regeneration are important topics in neurological diseases. There are limited options for therapeutic interventions in neurological diseases that provide simultaneous spatial and temporal control of neurons. This drawback increases side effects due to non-specific targeting. Optogenetics is a technology that allows precise spatial and temporal control of cells. Therefore, this technique has high potential as a therapeutic strategy for neurological diseases. Even though the application of optogenetics in understanding brain functional organization and complex behaviour states have been elaborated, reviews of its therapeutic potential especially in neurodegeneration and regeneration are still limited. This short review presents representative work in optogenetics in disease models such as spinal cord injury, multiple sclerosis, epilepsy, Alzheimer’s disease and Parkinson’s disease. It is aimed to provide a broader perspective on optogenetic therapeutic potential in neurodegeneration and neural regeneration. Keywords: light-activated proteins, neural plasticity, spinal cord injury, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, neural engineering, memory retrieval, neuron inhibition, neuron activation, neural regeneration Introduction Optogenetics is a technology that combines optics with genetics to induce a precise gain or loss-of- function in cells or tissue by applying light (Yizhar et al., 2011a). This biological technique involves: 1) engineering a gene that must be delivered in a cell specific manner and expressed at adequate levels, 2) developing a mode to deliver light for in vitro and in vivo studies, and 3) detecting the effect of optogenetics (i.e., dendritic density, immunofluorescence, electrophysiology, behaviour studies) (Yizhar et al., 2011a). This light-sensitive technology has revolutionized the study of neuroscience with single-cell https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607808/?report=printable 1/25 3/13/2018 Optogenetics and its application in neural degeneration and regeneration and millisecond precision control of neurons (Deisseroth et al., 2006; Deisseroth, 2011). Accurate spatial and temporal control is especially important to a system as complex as the nervous system, containing a network of billions of cells. Current methods for neurological treatment involve targeting the nervous system with deep brain stimulation (DBS) and pharmacologic therapy (Oluigbo et al., 2012; Connolly and Lang, 2014). While DBS provides precise temporal control of neurons, it lacks spatial specificity. On the other hand, pharmacologic therapy can give spatial specificity, but it lacks temporal control of cellular processes (Li et al., 2012). Consequently, it is challenging for the neuroscience field to create a technique with these dual features. In the early 1970s, Francis Crick postulated that the field of neuroscience needed a tool that could be used to control neurons with cellular and temporal precision (Crick, 1979). Crick suggested light activation of neurons may be the solution to these drawbacks. It took nearly three decades to achieve what he had envisioned with the introduction of optogenetics to the study of the nervous system (Boyden et al., 2005). This review aims to briefly, yet concisely, introduce optogenetics and summarize its use as a tool to understand pathological circuitry and a possible treatment for neurological diseases. Major Components of Optogenetics Optogenetics works by transducing light-stimulated electrical currents directly into specific cells (Terakita, 2005). To achieve this purpose, this technique is comprised of three major components: 1) light-activated proteins, 2) light, and 3) mode of delivery. Light-activated proteins Light-activated proteins were first discovered approximately 40 years ago. There was the discovery of bacteriorhodopsin (proton pump) in 1971, halorhodopsin (chloride pump) in 1979 (Oesterhelt and Stoeckenius, 1971; Matsuno-Yagi and Mukohata, 1977), and channelrhodopsin-1 (proton channel) and -2 (cation channel) in 2002 and 2003 (Nagel et al., 2002, 2003), respectively. These channels and pumps called opsins are microbial 7-transmembrane domain proteins containing trans-retinal cofactors that are activated upon light exposure. In general, these microbial opsins have the common characteristic of directly inducing electrical currents into cells upon light activation. This feature is different from rhodopsin (opsin found in the retina of vertebrates), which indirectly transduces electrical current via intracellular G-proteins (Oesterhelt and Stoeckenius, 1971; Stryer, 1986). Despite their common role as cellular electrical transducers, each of these prokaryotic opsins brings about different effects on membrane potential upon activation with light. Upon light-induced electrical transduction, some opsins such as halorhodopsin (HR) hyperpolarize the membrane potential whereas other opsins such as channelrhodopsin (ChR) depolarize the membrane potential (Figure 1) (Zhang et al., 2006). Halorhodopsin hyperpolarizes the membrane potential by pumping chloride ions into cells, resulting in spiking and neurotransmission inhibition, and ChR depolarizes cell membranes by allowing cations to diffuse into the cells by an electrochemical gradient, which could induce an action potential (Nagel et al., 2003; Kikukawa et al., 2015). This is especially applicable in neurons because of their electrophysiological properties of generating action potentials. Initially, although the optogenetics method seemed revolutionary, there was a lot of scepticism about its application in neuroscience. There were concerns about whether photocurrents, which are currents induced by photons, would be too weak and slow to activate and inactivate neurons with millisecond precision. Moreover, it was thought that opsins may be toxic or not expressed at high enough levels in neurons to mediate a desired effect. Since opsins require trans-retinal cofactors for activation, it was postulated that optogenetics would require a multicomponent delivery similar to the novel molecular strategies, which were engineered at the time (Zemelman et al., 2002; Banghart et al., 2004; Deisseroth, 2011). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607808/?report=printable 2/25 3/13/2018 Optogenetics and its application in neural degeneration and regeneration The challenges of optogenetics application in neuroscience were overcome by Boyden et al. in 2005 (Boyden et al., 2005). Boyden’s group delivered the first opsin into neurons by transfecting cultured hippocampal cells with lentivirus containing channelrhodopsin-2 (ChR2). In their study, they showed activation of neurons within milliseconds of light stimulation, synaptic neurotransmission, and neuronal spike trains resembling normal neuron electrophysiology. A significant observation was that cell health and electrophysiology properties were not affected by ChR2 expression. Furthermore, since retinoids were found present in sufficient amounts in mature mammalian brains, this conferred optogenetics as a single- component strategy to control neuronal activity (Deisseroth et al., 2006; Zhang et al., 2006). Complementary tools that could inhibit neuronal activity were then introduced following the discovery of natronobacterium pharaonic halorhodopsin (NpHR) (Han and Boyden, 2007) and a new class of inhibitory opsins called archaerhodopsin, which are outward proton pumps (Chow et al., 2010). Since the serendipitous application of optogenetics to neural systems, the field has vastly expanded (Boyden, 2011). However, the introduction of optogenetics to neuroscience has not been without its challenges. For example, there were challenges in increasing the cell membrane transport of NpHR since it was observed to accumulate intracellularly at high expression levels (Gradinaru et al., 2007). To increase its cell surface expression, the C-terminal endoplasmic reticulum (ER) export peptide sequence from Kir2.1 channel was added, which resulted in the synthesis of the opsin enhanced natronobacterium pharaonic halorhodopsin (eNpHR) (Gradinaru
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